LB: Multimodal Non-Invasive Biomarker Characterization of Structural and Functional Alterations in ADSS1 Myopathy

Topic:

Translational Research

Poster Number: 500 LBM

Author(s):

MERVE KOÇ YEKEDÜZ, MD, Harvard Medical School and Ankara University Faculty of Medicine, Raquel van Gool, Harvard Medical School, Hanne van der Heijden, Harvard Medical School, Buket Sonbas Cobb, Harvard Medical School, Nehal Shah, Harvard Medical School, Georgina Johnson, The University of Melbourne, Cara A. Timpani, PhD, Victoria University, Julie Shulman, Boston Children’s Hospital, Vanessa Rameh, Harvard Medical School, Evan E. Hsu, Harvard Medical School, Courtney LeSon, Harvard Medical School, Pui Y. Lee, Harvard Medical School, Adam P. Vogel, The University of Melbourne, Walla Al-Hertani, Children’s Hospital of Orange County, Hyung Jun Park, Yonsei University College of Medicine, Emma Rybalka, PhD, Institute for Health and Sport and Australian Institute for Musculoskeletal Science, Seward B. Rutkove, MD, Harvard Medical School, Jaymin Upadhyay, Harvard Medical School

Background:
Adenylosuccinate synthetase 1 (ADSS1) myopathy is an ultra-rare neuromuscular disorder characterized by progressive muscle dysfunction, with limited biomarkers available to comprehensively capture disease expression and functional burden.

Objectives:
This study aimed to employ a non-invasive, multimodal biomarker approach to phenotype fine-motor skills, speech production, and cognitive function in adults with ADSS1 myopathy compared with healthy controls.

Results:
Five adults with ADSS1 myopathy and five age- and sex-matched healthy controls underwent comprehensive assessments, including motor performance testing, speech and cognitive batteries, patient-reported outcomes, electrical impedance myography (EIM), musculoskeletal magnetic resonance imaging (MRI), and plasma proteomics. Compared with healthy controls, individuals with ADSS1 demonstrated reduced performance on the 9-Hole Peg Test and grip strength, along with lower self-reported mobility. Speech analysis revealed asthenia (p=0.02), reduced intelligibility (p=0.008), and poorer voice quality during sustained vowel production (p=0.03). Cognitive performance was preserved. EIM showed higher resistance and lower reactance and phase across upper and lower extremities, consistent with impaired muscle health and large effect sizes (Cliff’s δ=0.5–0.9). MRI demonstrated intramuscular fat infiltration, predominantly in posterior thigh compartments such as the biceps femoris. Proteomic analysis revealed significantly reduced Neurotrophin-3 (NTF3) levels (p=0.04) in the ADSS1 cohort, which were associated with poorer hand motor performance and adverse EIM parameters.

Conclusions:
Multimodal, non-invasive phenotyping integrating functional assessments, EIM, MRI, and plasma proteomics provides sensitive markers of neuromuscular dysfunction in ADSS1 myopathy. This approach offers a robust framework for refined disease characterization and supports biomarker-driven strategies for longitudinal monitoring in this ultra-rare condition.